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Somatic mosaicism and variant frequency detected by next-generation sequencing in
X-linked Alport syndrome
#MMPMID26014433
Fu XJ
; Nozu K
; Kaito H
; Ninchoji T
; Morisada N
; Nakanishi K
; Yoshikawa N
; Ohtsubo H
; Matsunoshita N
; Kamiyoshi N
; Matsumura C
; Takagi N
; Maekawa K
; Taniguchi-Ikeda M
; Iijima K
Eur J Hum Genet
2016[Mar]; 24
(3
): 387-91
PMID26014433
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X-linked Alport syndrome (XLAS) is a progressive, hereditary nephropathy.
Although men with XLAS usually develop end-stage renal disease before 30 years of
age, some men show a milder phenotype and develop end-stage renal disease later
in life. However, the molecular mechanisms associated with this milder phenotype
have not been fully identified. We genetically diagnosed 186 patients with
suspected XLAS between January 2006 and August 2014. Genetic examination
involved: (1) extraction and analysis of genomic DNA using PCR and direct
sequencing using Sanger's method and (2) next-generation sequencing to detect
variant allele frequencies. We identified somatic mosaic variants in the type VI
collagen, ?5 gene (COL4A5) in four patients. Interestingly, two of these four
patients with variant frequencies in kidney biopsies or urinary sediment cells of
?50% showed hematuria and moderate proteinuria, whereas the other two with
variant frequencies of <50% were asymptomatic or only had hematuria. De novo
variants can occur even in asymptomatic male cases of XLAS resulting in
mosaicism, with important implications for genetic counseling. This is the first
study to show a tendency between the variant allele frequency and disease
severity in male XLAS patients with somatic mosaic variants in COL4A5. Although
this is a very rare status of somatic mosaicism, further analysis is needed to
show this correlation in a larger population.
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